Dietary lycopene decreases the initiation of liver preneoplastic foci by diethylnitrosamine in the rat

Abstract

To test whether carotenoids can modulate the initiation of liver preneoplasia by diethylnitrosamine (DEN) or by 2-nitropropane (2-NP) in a sequential protocol of hepatocarcinogenesis, male weanling rats were fed for three or four weeks (respectively) diets containing beta-carotene, canthaxanthin, astaxanthin, or lycopene (300 mg/kg diet) or an excess of vitamin A (15,000 retinol equivalents/kg diet) or were treated intraperitoneally with 3-methylcholanthrene. During this period, all rats were injected intraperitoneally with the initiator carcinogen, either 2-NP (6 times at 100 mg/kg body wt) or DEN (once at 100 mg/kg body wt). Three weeks after the termination of carotenoid or vitamin A feeding, the rats received 50 ppm of 2-acetylaminofluorene in their diet for a two-week period, in the middle of which they were subjected to two-thirds partial hepatectomy, and were sacrificed one week later. gamma-Glutamyl transpeptidase- and placental glutathione S-transferase-positive foci were detected in frozen-cut liver sections by histochemical and histoimmunochemical techniques, respectively. None of the treatments tested had any influence on the number and size of preneoplastic liver foci induced by 2-NP, despite a significant incorporation and persistence in the liver of the carotenoids, except astaxanthin, and of supplemental vitamin A. Feeding the rats lycopene significantly decreased the size of gamma-glutamyl transpeptidase- and glutathione S-transferase-positive foci induced by DEN (by 64% and 65%, respectively), as well as the fraction of liver volume occupied by foci (by 84% and 79%, respectively), but did not significantly reduce their number. The other carotenoids, including beta-carotene, exerted no significant effects on DEN-induced preneoplasias. Lycopene does not appear to act through its antioxidant properties, but rather through its modulating effect on the liver enzyme activating DEN, cytochrome P-450 2E1.

Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

“…Astorg et al [153,154] demonstrated in two studies that β-carotene failed to exhibit any chemopreventive activity against a variety of chemically-induced hepatocarcinogenesis models in rats. This includes absence of effects on the number and size of preneoplastic foci in male Wistar rats that were induced with DENA/2-AAF, DENA or 2-nitropropane (2-NP) to develop preneoplastic liver foci.…”

“…However, only two studies were successful in achieving any beneficial effects exerted by these carotenoids. Astorg et al [153,154] conducted two studies with canthaxanthin and astaxanthin, and did not observe any preventive effects exerted by them against chemically-induced hepatocarcinogenesis in male Wistar rats. A dietary treatment regimen of either carotenoid at 300 mg/kg for 3 wk did not modify the number and size of GGT or GSTp foci in rats subjected to DENA or 2-NP hepatocarcinogenic regimen.…”

“…Diet Astorg et al [154] Did not modify DENA-initiated and PCBpromoted hepatocarcinogene-sis in female Sprague-Dawley rats 0.5%; 12 wk Diet Tharappel et al [155] Inhibited the development of preneoplastic foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats 70 mg/kg; alternate d for 2-8 wk po Moreno et al [156] Reduced the generation of nodules and GGT foci induced by DENA/2-AAF in male Wistar rats 70 mg/kg; 8 wk po Moreno et al [157] Decreased the incidence and total number of GGT foci and nodules in DENA-initiated and 2-AAFpromoted hepatocarcinogenesis in male Wistar rats…”

“…Diet Astorg et al [154] Attenuated the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats ↓DNA strand breaks 70 mg/kg per day; 8 wk po Toledo et al [181] Decreased the number of GSTp foci in DENAinitiated and PCB-promoted hepatocarcinogenesis in female Sprague-Dawley rats 1%; 12 wk Diet Tharappel et al [155] Inhibited DENA-initiated and NASH-promoted GSTp foci development in male Sprague-Dawley rats ↓PCNA; ↓cyclinD1; ↓lipid peroxidation; ↑Nrf2; ↑HO-1; ↓pERK; ↓NF-κB p65…”

“…Diet Sarkar et al [167] Reduced the incidence, total number, multiplicity and size of nodules in DENA/PB hepatocarcinogenesis in male Sprague-Dawley rats ↓GSH; ↓GGT; ↓GPX; ↑CYP; ↑GST 500 mg/kg; 4-20 wk po Bishayee et al [168] Decreased the number and size of GSTp foci in IQ-initiated and PB-promoted hepatocarcinogenesis in male Fischer rats 0.02%; 8 d Diet Tsuda et al [169] Inhibited the development of GSTp foci and HCC induced by EE in female Wistar rats 250 mg/kg diet; 1-12 mo Diet Ogawa et al [170] Reduced the development of GSTp foci in Glu-P-1-induced hepato-carcinogenesis in male F344 rats 0.1%; 6 wk Diet Hirose et al [131] Inhibited carcinogen-DNA adduct formation induced by IQ in male F344 rats ↓CYP1A1; ↓CYP1A2 0.02%; 8 d Diet Uehara et al [171] Reduced the number of liver tumors in multiorgan carcinogenesis in male B6C3F1 mice 0.4 mg/mouse; three times a week for 24 wk po Tsuda et al [152] Reduced AFB1-induced hepato-carcinogenesis in male Wistar rats 300 ppm; 3 wk Diet Gradelet et al [172] Decreased the number and volume of GSTp foci initiated by AFB1 in male Wistar rats 300 mg/kg diet; 3 wk Diet Gradelet et al [173] Inhibited liver tumor formation induced by DMBA in both male and female toads 0.05 mg/toad; twice a week for 12 wk sc Sadek et al [174] Suppressed the formation of GSTp foci and nodules initiated with DENA and promoted by PB in male Sprague-Dawley rats ↓GSH; ↓GST; ↑O2 consumption 120 mg/kg; 16 wk Diet Chattopadhyay et al [175] Reversed histomorphological changes during DENA-induced hepatocarcinogenesis in male Sprague-Dawley rats [153] Failed to exhibit any effect on 2-NP-or DENAinitiated liver carcinogenesis in male Wistar rats 300 mg/kg diet; 3 wk Diet Astorg et al [154] Attenuated the number and size of GSTp foci induced by AFB1/2-AAF in male Wistar rats ↓DNA single strand breaks 300 ppm; 3 wk Diet Gradelet et al [172] Reduced initiation of liver carcinogenesis by AFB1 in male Wistar rats ↓AFB1-DNA binding; ↓DNA single strand breaks; ↑AFB1 metabolism 300 mg/kg diet; 3 wk Diet Gradelet et al [173] β-Ionone Reduced the incidence, number and size of GSTp foci and nodules in the initial phase of DENA/2-AAF hepatocarcinogenesis in male Wistar rats ↓cell proliferation; ↓plasma cholesterol; ↓DNA damage 80 160 mg/kg; 7 wk po de Moura Espíndola et al [140] Inhibited GSTp foci and nodules during promotional phase of DENA/2-AAF hepatocarcino-genesis in male Wistar rats ↓cell proliferation; ↓HMGCoA reductase 160 mg/kg; 5 wk po Cardozo et al [130] Lutein Reduced the number and size of GSTp foci initiated by DENA and promoted with 2-AAF in male Wistar rats ↓DNA strand breaks 70 mg/kg per day; 8 wk po Toledo et al [181] Reduced the size of nodules during the promotional phase of DENA/2-AAF hepatocar...…”